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HIL-18BP remedy did not significantly decrease the synovial inflammation score in the first arthritic paw at any of the tested doses (Table 1). Interestingly, when the other paws (initial arthritic paw excluded) were analyzed, remedy with 1 mg/kg and 3 mg/kg rhIL-18BP substantially lowered the synovial inflammation score (P 0.05). Macroscopic inflammation, measured by the progression of paw Complement Component 3 Proteins Source swelling, was reduced considerably by the greater doses of rhIL-18BP (1 mg/kg and 3 mg/kg; P = 0.04). Even so, the treatments with all the decrease doses of 0.25 mg/kg and 0.5 mg/kg rhIL-18BP had no important effect on this parameter. Reduction of serum IL-6 levels after IL-18 neutralization in vivo. To obtain some insight into the mechanism of action in the course of IL-18 neutralization, serum levels of IL-6, TNF-, IL-1, and IFN- were measured within the treated animals in the time of sacrifice. Levels of IL-6 within the sera with the animals treated with 1 and 3 mg/kg rhIL-18BP were considerably decreased (P = 0.026 and P = 0.029, respectively) compared with saline-treated CIA mice (Figure 5b). Similarly, the levels of bioactive mIL-6 have been also significantly reduced soon after anti L-18 IgG therapy (P 0.01), as shown in Figure 5a. Circulating levels from the other cytokines tested had been under the limit of detection. rhIL-18BP decreases IL-18 nduced TNF-, IL-6, and IFN- secretion by peritoneal macrophages in vitro. The contribution of macrophage-derived proinflammatory cytokines in CIA is properly established (23, 28). Thus, to investigate a potential mode of action of rhIL-18BP, the ability of rhIL-18BP to control the production of proinflammatory cytokines like TNF-, IL-6, and IFN- specifically by macrophages was investigated. IL-18 directly promoted TNF- and IL-6 secretion by peritoneal macrophages; in contrast, secretion of IFN- was induced only by the combination of IL-18 and IL-12. As hypothesized, TNF- and IL-6 levels were decreased to basal values in the Viral Proteins Recombinant Proteins presence of rhIL-18BP (Figure 6, a and b; P = 0.001 and P = 0.0007, respectively). Interestingly, the inhibitory effect of rhIL-18BP was also observed when these cytokines were induced by the combination of IL- Volume 108 NumberDecemberFigure 3 Neutralization of endogenous IL-18 decreases cartilage destruction in CIA mice. (a) Erosion scores of arthritic joints soon after treatment with two mg/mouse of handle IgG (squares), anti L-18 IgG (triangles), and 0 mg/kg (inverted triangles), 0.25 mg/kg (diamonds), 0.5 mg/kg (circles), 1 mg/kg (open squares), and 3 mg/kg (triangles) of rhIL-18BP, as indicated. (b and c) Quantification of serum levels of COMP, a marker of cartilage turnover, soon after treatment with 2 mg of regular rabbit IgG (squares) or anti IL-18 IgG (triangles) (b), and with saline (0 rhIL-18BP) (squares) or with 1 mg/kg (triangles) and three mg/kg (inverted triangles) rhIL-18BP (c). P 0.05, P = 0.0023, P = 0.0006, treated versus control groups.and IL-12 (Figure 6, a and b; P = 0.0009 and P = 0.0004, respectively). IFN- levels were also significantly decreased within the presence of rhIL-18BP (Figure 6c; P = 0.0001). These information demonstrate that neutralization of IL-18 activity benefits in decreased production of TNF-, IL-6, and IFN- by macrophages, offering a prospective explanation for the protective effect observed in vivo.therapeutic strategy protects joints from further destruction. The disease-modifying home from the treatment was demonstrated by a significant reduce in cartilage erosion scores and reduction in the.